U.S. patent number 5,190,935 [Application Number 07/773,950] was granted by the patent office on 1993-03-02 for vitamin d analogues.
This patent grant is currently assigned to Leo Pharmaceutical Products Ltd.. Invention is credited to Ernst T. Binderup, Martin J. Calverley.
United States Patent |
5,190,935 |
Binderup , et al. |
March 2, 1993 |
**Please see images for:
( Certificate of Correction ) ** |
Vitamin D analogues
Inventors: |
Binderup; Ernst T.
(T.ang.strup, DK), Calverley; Martin J. (Herlev,
DK) |
Assignee: |
Leo Pharmaceutical Products
Ltd. (Ballerup, DK)
|
Family
ID: |
10659806 |
Appl.
No.: |
07/773,950 |
Filed: |
November 19, 1991 |
PCT
Filed: |
July 04, 1990 |
PCT No.: |
PCT/DK90/00168 |
371
Date: |
November 19, 1991 |
102(e)
Date: |
November 19, 1991 |
PCT
Pub. No.: |
WO91/00855 |
PCT
Pub. Date: |
January 24, 1991 |
Foreign Application Priority Data
|
|
|
|
|
Jul 10, 1989 [GB] |
|
|
8915770 |
|
Current U.S.
Class: |
514/167;
552/653 |
Current CPC
Class: |
A61P
11/00 (20180101); A61P 29/00 (20180101); A61P
37/00 (20180101); C07F 9/117 (20130101); A61P
17/00 (20180101); A61P 9/12 (20180101); C07C
401/00 (20130101); A61P 35/00 (20180101) |
Current International
Class: |
C07C
401/00 (20060101); C07F 9/00 (20060101); C07F
9/117 (20060101); A61K 031/59 (); C07J
175/00 () |
Field of
Search: |
;552/653 ;514/167 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Calverley, M. J. Tetrahedron, 43 (20) pp. 4609-4619 (1987). .
WO, A1, 85093939 (Sep. 12, 1985) see whole document. .
Biochemical Pharmachology, vol. 37, No. 5, 1988 Lise Binderup et
al: "Effects of a novel vitamin D analogue MC903 on cell
proliferation and differentiation in vitro and on calcium
metabolism in vivo", see page 889-895..
|
Primary Examiner: Mars; Howard T.
Assistant Examiner: Kestler; Kimberly J.
Attorney, Agent or Firm: Cushman, Darby & Cushman
Claims
What we claim is:
1. A compound of the formula I ##STR13## in which formula, n is 2
or 3, m is 0 or an integer from 1 -4; R.sup.1 and R.sup.2 (which
may be the same or different) stand for hydrogen or C.sub.1
-C.sub.8, hydrocarbyl indicating the residue after removal of a
hydrogen atom from a straight, branched or cyclic saturated or
unsaturated hydrocarbon, or taken together with the carbon bearing
the hydroxyl group (starred in formula I), R.sup.1 and R.sup.2 can
form a saturated or unsaturated C.sub.3 -C.sub.8 carbocyclic ring;
in addition, R.sup.1 and/or R.sup.2 and/or one of the m carbons
designated by the ". " may be optionally substituted with one or
more chlorine or fluorine atom(s); and finally one of the carbons
designated "." may optionally be substituted by one or two C.sub.1
-C.sub.2 alkyl group(s); and derivatives of the compounds pounds of
formula I in which one or more hydroxy have been transformed into
-O-acyl or -O-glycosyl or phosphate ester groups; such masked
groups being hydrolyzable in vivo; and other prodrugs thereof.
2. A diastereoisomer of a compound according to claim 1, in pure
form; or a mixture of diastereoisomers of a compound according to
claim 1.
3. A compound according to claim 1 selected from the groups
consisting of the 20(R) and 20(S) isomers of:
1(S),3(R)-Dihydroxy-20-(5'-hydroxy-5'-methyl-hexa-1'(E),3'(E)-dien-1'-yl)-9
,10-secopregna-5(Z),7(E),-10(19)-triene;
1(S),3(R)-Dihydroxy-20-(5'-ethyl-5'hydroxy-hepta-1'(E),3'(E)-dien-1'-yl)-9,
10-secopregna-5(Z),7(E),-10(19)-triene;
1(S),3(R)-Dihydroxy-20-(6'-hydroxy-hexa-1'(E),-3'(E)-dien-1'-yl)-9,10-secop
regna-5(Z),7(E),-10(19)-triene;
1(S),3(R)-Dihydroxy-20-(5'-cyclopropyl-5'-hydroxy-penta-1'(E),3'(E)-dien-1'
-yl)-9,10-secopregna-5(Z),-7(E),10(19)-triene (5'(R) and 5'(S)
isomers);
1(S),3(R)-Dihydroxy-20-(6'-hydroxy-6'-methyl-hepta-1'(E),3'(E)-dien-1'-yl)-
9,10-secopregna-5(Z),7(E),-10(19)-triene;
4. A pharmaceutical composition containing an effective amount of
one or more of the compounds of claim 1, together with
pharmaceutically acceptable, non-toxic carriers and/or auxiliary
agents.
5. A pharmaceutical composition according to claim 4 for topical
use containing from 0.1-100 .mu.g/g of a compound of formula I.
6. A pharmaceutical composition according to claim 4 in dosage unit
form.
7. A dosage unit according to claim 6 containing from 0.01-100
.mu.g for oral and parenteral formulations of a compound of formula
I.
Description
This invention relates to a hitherto unknown class of compounds
which shows antiinflammatory and immunomodulating effects as well
as strong activity in inducing differentiation and inhibiting
undesirable proliferation of certain cells, including cancer cells
and skin cells, to pharmaceutical preparations containing these
compounds, to dosage units of such preparations, and to their use
in the treatment and prophylaxis of a number of disease states
including diabetes mellitus, hypertension, acne, alopecia, skin
ageing, imbalance in the immune system, inflammatory diseases such
as rheumatoid arthritis and asthma as well as diseases
characterized by abnormal cell differentiation and/or cell
proliferation such as e.g. psoriasis and cancer.
The compounds of the invention constitute a novel class of vitamin
D analogues and are represented by the general formula I ##STR2##
in which formula (and also throughout the remainder of this
disclosure), n is 2 or 3, m is 0 or an integer from 1-4; R.sup.1
and R.sup.2 (which may be the same or different) stand for hydrogen
or C.sub.1 -C.sub.8 -hydrocarbyl, or, taken together with the
carbon bearing the hydroxyl group (starred in formula I), R.sup.1
and R.sup.2 can form a saturated or unsaturated C.sub.3 -C.sub.8
carbocyclic ring. In addition, R.sup.1 and/or R.sup.2 and/or one of
the m carbons designated by the "." may be optionally substituted
with one or more chlorine or fluorine atom(s); and finally one of
the carbons designated "" may optionally be substituted by one or
two C.sub.1 -C.sub.2 alkyl group(s).
In the context of this invention, the expression hydrocarbyl
radical indicates the residue after removal of a hydrogen atom from
a straight, branched or cyclic saturated or unsaturated
hydrocarbon.
Examples of R.sup.1 and R.sup.2 when taken separately include
(apart from hydrogen), but are not limited to, methyl,
trifluoromethyl, ethyl, vinyl, normal-, iso- and cyclopropyl, and
1-methylvinyl
Examples of R.sup.1 and R.sup.2 when taken together include di-,
tri-, tetra- and penta-methylene.
As can be seen from formula I, the compounds of the invention
include diastereoisomeric forms (e.g. E or Z configuration of a
side chain double bond; R or S configuration at C-20 and at the
starred carbon atom depending on the meanings of R.sup.1 and
R.sup.2). The invention covers all these diastereoisomers in pure
form and also mixtures of diastereoisomers. It should be noted,
however, that our investigations indicate a notable difference in
activity between the stereoisomeric forms. In addition, derivatives
of I in which one or more of the hydroxy groups are masked as
groups which can be reconverted to hydroxy groups in vivo are also
within the scope of the invention ("bioreversible derivatives or
pro-drugs of I").
The term "bioreversible derivatives or prodrugs of I" includes but
is not limited to. derivatives of the compounds of formula I in
which one or more hydroxy groups have been transformed into -O-acyl
or -O-glycosyl or phosphate ester groups, such masked groups being
hydrolyzable in vivo.
Also within the scope of this disclosure is another type of prodrug
of I in which the hydroxyl group at the starred carbon atom is
replaced by a hydrogen atom. These compounds are relatively
inactive in vitro, but are converted to active compounds of formula
I by enzymatic hydroxylation after administration to the
patient.
It has recently been shown that 1.alpha.,25-dihydroxy-vitamin
D.sub.3 (1,25(OH).sub.2 D.sub.3) influences the effects and/or
production of interleukins (Immunol. Lett. 17, 361-366 (1988)),
indicating the potential use of this compound in the treatment of
diseases characterized by a dysfunction of the immune system, e.g.
autoimmune diseases, host versus graft reactions, and rejection of
transplants or other conditions characterized by an abnormal
interleukin-1 production, e.g. inflammatory diseases such as
rheumatoid arthritis and asthma.
It has also been shown that 1,25(OH).sub.2 D.sub.3 is able to
stimulate the differentiation of cells and inhibit excessive cell
proliferation (Abe, E. et al, Proc. Natl. Acad. Sci., U.S.A. 78,
4990-4994 (1981)), and it has been suggested that this compound
might be useful in the treatment of diseases characterized by
abnormal cell proliferation and/or cell differentiation such as
leukemia, myelofibrosis and psoriasis.
Also, the use of 1,25(OH).sub.2 D.sub.3, or its pro-drug
1.alpha.-OH-D.sub.3, for the treatment of hypertension (Lind, L. et
al, Acta Med. Scand. 222, 423-427 (1987)) and diabetes mellitus
(Inomata, S. et al, Bone Mineral 1, 187-192 (1986)) has been
suggested. Another indication for 1,25(OH).sub.2 D.sub.3 is
suggested by the recent observation of an association between
hereditary vitamin D resistance and alopecia: treatment with
1,25(OH).sub.2 D.sub.3 may promote hair growth (Lancet, Mar. 4,
1989, p. 478). Finally, the fact that topical application of
1,25(OH).sub.2 D.sub.3 reduces the size of sebaceous glands in the
ears of male Syrian hamsters suggests that this compound might be
useful for the treatment of acne (Malloy, V. L. et al., the
Tricontinental Meeting for Investigative Dermatology, Washington,
1989).
However, the therapeutic possibilities in such indications of
1,25(OH).sub.2 D.sub.3 are severely limited by the well known
potent effect of this hormone on calcium metabolism; elevated blood
concentrations will rapidly give rise to hypercalcemia. Thus, this
compound and its potent synthetic analogues are not completely
satisfatory for use as drugs in the treatment of e.g. psoriasis,
leukemia or immune diseases which may require continuous
administration of the drug in relatively high doses.
A number of vitamin D analogues have recently been described which
show some degree of selectivity in favour of the cell
differentiation inducing/cell proliferation inhibiting activity as
compared with the effect on calcium metabolism.
Thus, the vitamin D.sub.3 analogue, MC 903, containing a
22,23-double bond, a 24-hydroxy group and in which the carbon atoms
25,26 and 27 are incorporated in a three membered ring, is a potent
inducer of cell differentiation and inhibitor of cell proliferation
which shows only moderate activity on calcium metabolism in vivo
(Binderup, L. and Bramm, E., Biochemical Pharmacology 37, 889-895
(1988)). However, this selectivity is not paralleled by in vitro
studies, which show that MC 903 binds equally well as
1,25(OH).sub.2 D.sub.3 to the intestinal vitamin D receptor. It may
therefore be that the low in vivo activity on calcium metabolism of
MC 903 is due to a rapid metabolism of the compound, thus limiting
the potential of this compound for systemic use.
24-Homo-1,25-dihydroxyvitamin D.sub.3 and
26-homo-1,25-dihydroxyvitamin D.sub.3 (together with their
22,23-didehydroanalogues) (Ostrem, V. K.; Tanaka, Y.; Prahl, J.;
DeLuca, H. F.; and Ikekawa, N.; Proc. Natl. Acad. Sci. USA 84,
2610-14 (1987)) have been claimed to have the same binding affinity
as 1,25(OH).sub.2 D.sub.3 to both the rat and chicken intestinal
receptor and the receptor in a human myeloid leukemia cell line
(HL-60), and yet to be 10-fold more potent than l,25(OH).sub.2
D.sub.3 in inducing differentiation of HL-60 cells in vitro. In
vivo, these compounds are respectively "significantly less potent"
and "more potent" than 1,25(OH).sub.2 D.sub.3 in calcium metabolism
assessments.
26,27-Dimethyl-1.alpha.,25-dihydroxyvitamin D.sub.3 has been
synthesized, but the published information regarding its biological
acitivities is contradictory. (Sai, H.; Takatsuto, S.; Hara, N.;
and Ikekawa, N.; Chem. Pharm. Bull. 33, 878-881 (1985) and Ikekawa,
N.; Eguchi, T.; Hara, N.; Takatsuto, S.; Honda, A.; Mori, Y.; and
Otomo, S.; Chem. Pharm. Bull. 35, 4362-4365 (1987)). The closely
related 26,27-diethyl-1.alpha.,25-dihydroxyvitamin D.sub.3 is also
reported by these authors; in this case as having "aImost no
vitamin D activity" (i.e. calcium metabolism effects) while being
10-fold more potent than 1,25(OH).sub.2 D.sub.3 in inducing cell
differentiation.
The fact that there are only small structural differences between
the above compounds indicates that the present state of knowledge
does not allow prediction of the structure of vitamin D analogues
which will show a favourable degree of selectivity, as reflected by
a higher cell differentiating activity in vitro compared to the
binding affinity for intestinal vitamin D receptor in vitro.
Furthermore, the matter is complicated by the observation that
receptor binding affinities in vitro are not always paralleled by
in vivo studies, probably reflecting a pharmacokinetic difference
between the compounds.
The compounds of the present invention are distinguished
structurally from all vitamin D analogues which have been reported
to have potent effects on cell differentiation/proliferation by the
presence of a conjugated diene or triene moiety in the side
chain.
Corresponding compounds which have a saturated side chain or an
isolated double bond (22,23-didehydroderivatives) have been
disclosed in international patent application No. PCT/DK89/00079,
international filing date Apr. 7, 1989 and (for one pair of
examples) in the Ostrem et al, reference discussed above, but none
of these disclosures suggest methods for the incorporation of a
conjugated polyene system into the side chain. Our synthetic
studies have now opened up general routes to such polyene systems,
and it has been surprisingly found that this type of functionality
has an advantageous biological significance. Thus a particular
compound of formula I, when compared to the corresponding compound
in which all, or all but the 22,23-double bond, are saturated, is
observed to show one or more of the following advantages:
(a) more potent effects on cell differentiation/proliferation;
(b) a greater selectivity in favour of the potent effects on cell
differentiation/proliferation contra the effects on calcium
metabolism;
(c) more potent effects on the production and action of
interleukins;
(d) a greater selectivity in favour of the effects on interleukin
production and action contra the effects on calcium metabolism.
An additional advantage conferred on the compounds I by the
presence of the polyene moiety results from the more restricted
conformational freedom of the side chain: the compounds I of the
present invention are more readily obtained crystalline than the
corresponding side chain saturated or partially saturated
analogues.
The compounds of the invention are therefore especially suited for
both local and systemic treatment and prophylaxis of human and
veterinary disorders which are characterized by 1) abnormal cell
proliferation and/or cell differentiation, such as certain
dermatological disorders including psoriasis and certain cancer
forms, 2) an imbalance in the immune system, e.g in autoimmune
diseases, including diabetes mellitus, host versus graft reaction,
and rejection of transplants; and additionally for the treatment of
inflammatory diseases, such as rheumatoid arthritis and asthma.
Acne, alopecia, skin ageing (including photoageing), and
hypertension are other conditions which may be treated with the
compounds of the invention.
The present compounds may be used in combination with other
pharmaceuticals. In the prevention of graft rejection and graft
versus host reaction, a treatment with the present compounds may
advantageously be combined with e.g. a cyclosporin treatment.
Compounds I can be prepared from the vitamin D-derived aldehyde lj
[M. J. Calverley, Tetrahedron 43, 4609 (1987)]or lk, which may be
obtained by triplet-sensitized photoisomerization of lj, optionally
via the compounds 2 or 3 (Scheme 1). Schemes 2 to 4 illustrate
reactions for the conversion of these key intermediates to
compounds I in which n, m, R.sup.1 and R.sup.2 have various
meanings.
The exemplified key intermediates of types 2 and 3 are listed in
Table 1.
In the Schemes, the following abbreviations are used: ##STR3##
In the Notes to Schemes, appropriate aqueous work-up steps are
implicit. The absolute configuration at C-20 can be either R or S.
For explanation of the expression "side chain fragment", see
following text. ##STR4##
A key step in some of the syntheses as described is the reaction
with an intermediate (of type A' or B') which is obtained by
treatment of a side chain fragment of type A or B respectively)
either by conversion to an organometallic agent or to an ylide, as
appropriate.
All these types of reactions are well known in the art of
carbon-carbon bond formation in synthetic organic chemistry.
In general, the side chain fragments have the structure:
with the following meanings (the following standard abbreviations
are used throughout this disclosure: Et=ethyl; Hep=heptyl;
Me=methyl; Ph=phenyl; Pr=propyl THP=tetrahydro-4H-pyran-2-yl; THF
=tetrahydrofuran; Ts p-toluenesulphonyl;
DMF=N,N-dimethylformamide):
For type A, Z=ph.sub.3 P.sup.30 --CH.sub.2 --or Z=Q.sub.2
P(O)--CH.sub.2 --, where Q=methoxy, ethoxy or phenyl, and the
corresponding A' has Z=Ph.sub.3 P.sup.+ --CH.sup.- -- or Q.sub.2
P(O)--CHM-- (M=metal e.g. Li).
For type B, Z=PhS(O.sub.2)--CH.sub.2 --, and the corresponding B'
has Z=PhS(O.sub.2)--CHM--, where M=metal, e.g. Li.
R.sup.3 is optionally hydrogen or an alcohol protective group such
as tri(loweralkyl)silyl or THP. In the case where R.sup.3 =H in B,
then R.sup.5 =M M=metal, e.g. XMg or Li) in the derived B'.
Fragments of type A, A' or B are known compounds or readily
available as described for example in international patent
application No. PCT/DK89/00079, international filing date Apr. 7,
1989, and British patent application No. 8914963.7, filing date
Jun. 29, 1989. Some Examples are listed in Tables 2 and 3.
Some of these side chain fragements are converted (see Preparations
and Examples) to the appropraite compounds I via the intermediates
indicated in the Schemes. The intermediates are specified in Table
4 and the exemplified compounds I in Table 5.
Specific compounds I are also available by special reactions. For
example, the compound 112 (Table 5) is obtained by isomerisation of
MC 903 by treatment with trifluoroacetic anhydride, followed by
saponification.
TABLE 1 ______________________________________ Exemplified Key
intermediates prepared from Compounds 1a or 1b (Scheme 1) Formula
Compound Configuration of side Number x chain polyene*
______________________________________ 2aj 1 E 2ak 1 E 2aj 2 E,E
2aj; isomer A 3 E,E,E 2aj; isomer B 3 E,Z,E 3aj 1 E 2bj 2 E,E 2ak 3
E,E,E ______________________________________ *Reading from left to
right.
TABLE 2 ______________________________________ Some Specific Side
Chain Fragments (Type A and A') [ZC(O)R.sup.2 ] Compound
Number.sup.+ R.sup.2 Z ______________________________________ 4
CHMe.sub.2 Ph.sub.3.sup..sym. PCH.sup..crclbar. 5 y = 1 5 y = 2 5 y
= 3 5 y = 4 ##STR5## Ph.sub.3.sup..sym. PCH.sup..crclbar. 6
##STR6## Ph.sub.3.sup..sym. PCH.sup..crclbar. 7 ##STR7##
(EtO).sub.2 P(O)CH.sub.2 8 CMe.sub.3 Ph.sub.3.sup..sym.
PCH.sup..crclbar. 9 CHEt.sub.2 Ph.sub.3.sup..sym. PCH.sup..crclbar.
10 CH(n-Pr).sub.2 Ph.sub.3.sup..sym. PCH.sup..crclbar.
______________________________________ .sup.+ As referred to in the
Preparations
TABLE 3 ______________________________________ Some Specific Side
Chain Fragments (Type B) [PhS(O.sub.2)CH.sub.2
--(.degree.CH.sub.2).sub.m --C(R.sup.1)(R.sup.2)OR.s up.3 ]
Compound Formula Number.sup.+ m R.sup.1 R.sup.2 R.sup.3
______________________________________ 11 1 Me Me H 12 1 Et Et H 13
1 --(CH.sub.2).sub.2 -- THP 14 2 Et Et H 15 3 Me Me H 16 4 Me Me H
.sup. 17.sup.++ 1 (CH(Me)) Me Me H 18** 1 (CH(Me)) Me Me H
______________________________________ .sup.+ As referred to in the
Preparations .sup.++ S-Form **R-Form Unsubstituted CH.sub.2 unless
otherwise indicated by specifying an alternative meaning of
"(.degree.CH.sub.2)".
TABLE 4
__________________________________________________________________________
Compounds of Schemes 2-4 which are Intermediates in the Preparation
of Compounds I of Scheme 4 Configuration Compound of the Number
side chain Configuration (R = j or k) Type Scheme n m R.sup.1
R.sup.2 R.sup.3 polyene* at C-20
__________________________________________________________________________
101j III 2 2 -- -- ##STR8## -- E,E R 102j 103j II II 2 2 2 -- H
##STR9## -- E,E R 102k 103k II II 4 4 2 -- H ##STR10## -- E,E R
104j II 2 2 -- Me Me -- E,E R 104k II 4 2 -- Me Me H E,E R 105j II
2 2 -- Et Et -- E,E R 105k II 4 2 -- Et Et H E,E R 106j II 2 3 --
Me Me -- E,E,E R 107j V 3 2 1 Me Me H E,E R 107k II 4 2 1 Me Me H
E,E R 113j II 2 2 -- Me Me -- E,E S 113k II 4 2 -- Me Me H E,E S
114j II 2 2 -- Et Et -- E,E S 114k II 4 2 -- Et Et H E,E S 117j II
2 2 -- H H -- E,E S 117k II 4 2 -- H H H E,E S 119j II 2 2 -- Pr Pr
-- E,E R 119k II 4 2 -- Pr Pr H E,E R 121j II 2 2 -- H H -- E,E R
121k II 4 2 -- H H H E,E R 123k II 2 1 -- H H -- E R 124k II 2 3 --
Me Me -- E,E,E R 126k II 2 3 -- Et Et -- E,E,E R 128k II 2 3 -- H H
-- E,E,E R
__________________________________________________________________________
Note as for Table 3 *Reading from left to right NB Where identical
descriptions for two numbered compounds are given (e.g 102j and
103j) the compounds are distinguished only in their configuratio at
the starred carbon atom. These configurations give rise to two
series of compounds, referred to as "isomer A" and "isomer B" in
the Preparation and Examples.
TABLE 5
__________________________________________________________________________
Exemplified Compounds I Configuration Compound of side
Configuration Number m n R.sup.1 R.sup.2 chain polyene* at C-20
__________________________________________________________________________
108 109 0 2 H ##STR11## E,E R 110 0 2 Me Me E,E R 111 0 2 Et Et E,E
R 112 1 2 H H E,E R 115 0 2 Me Me E,E S 116 0 2 Et Et E,E S 118 0 2
H H E,E S 120 0 2 Pr Pr E,E R 122 0 2 H H E,E R 125 0 3 Me Me E,E,E
R 127 0 3 Et Et E,E,E R 129 0 3 H H E,E,E R 130 1 2 H H E,E S 131
132 0 2 H ##STR12## E,E S 133 1 2 Me Me E,E R 134 1 2 Me Me E,E S
135 1 2 Et Et E,E S 136 1 2 Et Et E,E R 137-38 1(CH(Me)) 2 Me Me
E,E R 139-40 1(CH(Me)) 2 Me Me E,E S
__________________________________________________________________________
Notes as for Table 4
Parallel reactions can be used to convert other side chain
fragments to the corresponding compounds I.
In cases where R.sup.1 .noteq.R.sup.2 in compounds II or V, the
isomers can be separated and the configuration at the starred
carbon atom can be inverted or equilibrated at this stage by
application of standard reactions.
The synthesis of the prodrugs of compounds I which lack the side
chain hydroxyl (at the starred carbon atom) may follow the route of
Scheme 3, using the appropriate side chain fragment of structure
Z--(.degree.CH.sub.2).sub.m ----CH(R.sup.1)(R.sup.2).
The present compounds are intended for use in pharmaceutical
compositions which are useful in the treatment of human and
veterinary disorders as described above.
The amount required of a compound of formula I (hereinafter
referred to as the active ingredient) for therapeutic effect will,
of course, vary both with the particular compound, the disease
state which is to be treated, the route of administration and the
mammal under treatment. The compounds of the invention can be
administered by the parenteral, intra-articular, enteral or topical
routes. They are well absorbed when given enterally and this is the
preferred form of administration in the treatment of systemic
disorders.
Conveniently, the active ingredient comprises from 0.1-100 .mu.g/g
for topical formulations and 0.05-100 .mu.g/g for oral and
parenteral formulations.
By the term "dosage unit" is meant a unitary, i.e. a single dose
which is capable of being administered to a patient as a physically
and chemically stable unit dose comprising either the active
material as such or a mixture of it with solid or liquid
pharmaceutical diluents or carriers.
The formulations, both for veterinary and for human medical use, of
the present invention comprise an active ingredient in association
with a pharmaceutically acceptable carrier therefore and optionally
other therapeutic ingredient(s). The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulations and not deleterious to the
recipient thereof.
The formulations include e.g. those in a form suitable for oral,
rectal, parenteral (including transdermal, subcutaneous,
intramuscular and intravenous), intra-articular and topical
administration.
The formulations may conveniently be presented in dosage unit form
and may be prepared by any of the methods well known in the art of
pharmacy. All methods include the step of bringing the active
ingredient into association with the carrier which constitutes one
or more accessory ingredients. In general, the formulations are
prepared by uniformly and intimately bringing the active ingredient
into association with a liquid carrier or a finely divided solid
carrier or both, and then, if necessary, shaping the product into
the desired formulation.
Formulations of the present invention suitable for oral
administration may be in the form of discrete units as capsules,
sachets, tablets or lozenges, each containing a predetermined
amount of the active ingredient; in the form of a powder or
granules; in the form of a solution or a suspension in an aqueous
liquid or non-aqueous liquid; or in the form of an oil-in-water
emulsion or a water-in-oil emulsion.
A tablet may be made by compressing or moulding the active
ingredient optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing, in a suitable
machine, the active ingredient in a free-flowing form such as a
powder or granules, optionally mixed by a binder, lubricant, inert
diluent, surface active or dispersing agent. Moulded tablets may be
made by moulding, in a suitable machine, a mixture of the powdered
active ingredient and suitable carrier moistened with an inert
liquid diluent.
Formulations for rectal administration may be in the form of a
suppository incorporating the active ingredient and a carrier such
as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration conveniently
comprise a sterile oily or aqueous preparation of the active
ingredient which is preferably isotonic with the blood of the
recipient.
Formulations suitable for intra-articular administration may be in
the form of a sterile aqueous preparation of the active ingredient
which may be in microcrystalline form, for example, in the form of
an aqueous microcrystalline suspension. Liposomal formulations or
biodegradable polymer systems may also be used to present the
active ingredient for both intra-articular and ophthalmic
administration.
Formulations suitable for topical administration include liquid or
semi-liquid preparations such as liniments, lotions, applicants,
oil-in-water or water-in-oil emulsions such as creams, ointments or
pastes; or solutions or suspensions such as drops; or as
sprays.
For asthma treatment, inhalation of powder, self-propelling or
spray formulations, dispensed with a spray can, a nebulizer or an
atomizer can be used. The formulations, when dispensed, preferably
have a particle size in the range of 10 to 100 .mu..
Such formulations are most preferably in the form of a finely
comminuted powder for pulmonary administration from a powder
inhalation device or self-propelling powder-dispensing
formulations. In the case of self-propelling solution and spray
formulations, the effect may be achieved either by choice of a
valve having the desired spray characteristics (i.e. being capable
of producing a spray having the desired particle size) or by
incorporating the active ingredient as a suspended powder in
controlled particle size. These self-propelling formulations may be
either powder-dispensing formulations or formulations dispensing
the active ingredient as droplets of a solution or suspension.
Self-propelling powder-dispensing formulations preferably comprise
dispersed particles of solid active ingredients, and a liquid
propellant having a boiling point below 18.degree. C. at
atmospheric pressure. The liquid propellant may be any propellant
known to be suitable for medicinal administration and may comprise
one or more C.sub.1 -C.sub.6 -alkyl hydrocarbons or halogenated
C.sub.1 -C.sub.6 -alkyl hydrocarbons or mixtures thereof;
chlorinated and flourinated C.sub.1 -C.sub.6 -alkyl hydrocarbons
are especially preferred. Generally, the propellant constitutes 45
to 99.9% w/w of the formulation whilst the active ingredient
constitutes 1 ppm to 0.1% w/w, of the formulation.
In addition to the aforementioned ingredients, the formulations of
this invention may include one or more additional auxiliary
ingredients such as diluents, buffers, flavouring agents, binders,
surface active agents, thickeners, lubricants, preservatives, e.g.
methyl hydroxybenzoate (including anti-oxidants), emulsifying
agents and the like.
The compositions may further contain other therapeutically active
compounds usually applied in the treatment of the above mentioned
pathological conditions.
The present invention further concerns a method for treating
patients suffering from one of the above pathological conditions,
said method consisting of administering to a patient in need of
treatment an effective amount of one or more compounds of formula
I, alone or in combination with one or more other therapeutically
active compounds usually applied in the treatment of said
pathological conditions. The treatment with the present compounds
and/or with further therapeutically active compounds may be
simultaneous or with intervals.
In the treatment of systemic disorders daily doses of from 0.01-100
.mu.g, preferably from 0.025-50 .mu.g, of a compound of formula I
are administered. In the topical treatment of dermatological
disorders, ointments, creams or lotions containing from 3.1-100
.mu.g/g, and preferably from 0.5-10 .mu.g/g, of a compound of
formula I are administered. The oral compositions are formulated,
preferably as tablets, capsules, or drops, containing from 0.01-100
.mu.g, preferably from 0.025-50 .mu.g, of a compound of formula I,
per dosage unit.
The invention will now be further described in the following
non-limiting Preparations and Examples:
PREPARATIONS AND EXAMPLES
General
The compounds referred to in the Preparations and Examples are to
be identified by number or letter with the corresponding formulae
in the Schemes and/or Tables. Ultra-violet spectra (.lambda.) were
measured for solutions in 96% ethanol. For nuclear magnetic
resonance spectra chemical shift values (.delta.) are quoted in
p.p.m. for deuteriochloroform solutions relative to internal
tetramethylsilane (.delta.=0) or chloroform (.delta.=7.25). The
value for a multiplet, either defined (doublet (d), triplet (t),
quartet (q)) or not (m) at the approximate mid point is given
unless a range is quoted (s=singlet, b .TM.broad) Coupling
constants (J) are given in Hertz, and are sometimes approximated to
the nearest unit.
Ether is diethyl ether, and was dried over sodium. THF was dried
over sodium-benzophenone. Petroleum ether refers to the pentane
fraction. Brine is saturated sodium chloride solution. Organic
solutions were dried over dried magnesium sulphate and concentrated
on a rotary evaporator at water aspirator pressure.
Preparation 1 Compound lak
A mixture of anthracene (0.10 g), triethylamine (20 mg), and the
compound laj (0.20 g) in toluene (15 ml), stirred under an
atmosphere of nitrogen in a Pyrex flask immersed in a water bath at
20.degree. C., was illuminated with radiation from a high pressure
Hg lamp (type: Hanau TQ 718Z2) for 30 minutes. The reaction mixture
was filtered and concentrated in vacuo to give a residue. This was
purified by chromatography (30 g silica gel, using 5% ether in
petroleum ether as eluant) to give lak; .delta.(300 MHz) 0.05 (12H,
bs), 0.56 (3H, s), 0.86 (18H, s), 1.12 (3H, d, J 7), 1.15-2.05
(13H, m), 2.20 (1H, dd), 2.35 (1H, m), 2.43 (1H, m), 2.81 (1H, bd),
4.18 (1H, m), 4.36 (1H, m), 4.84 (1H, m), 5.16 (1H, m), 6.01 (1H,
d, J 11), 6.21 (1H, d, J 11) and 9.57 (1H, d, J 3).
Preparation 2: Compound 2aj (x=1)
A stirred solution of laj (3.9 g), and
methoxycarbonylmethylene-triphenylphosphorane (4.6 g) in toluene
(40 ml) was heated under reflux for 3 hours. The reaction mixture
was cooled, filtered, and concentrated in vacuo. Purification of
the residue by chromatography (200 g silica gel; 5% ether in
petroleum ether as eluant) followed by recrystallization from
ether-methanol gave 2aj (x=1), as needles, m.p.
129.degree.-130.degree. C., .delta.(300 MHz) 0.05 (12H, bs), 0.56
(3H, s), 0.86 (9H, s), 0.89 (9H, s), 1.09 (3H, d, J 6.6), 1.1-2.1
(13H, m), 2.28 (2H, m), 2.54 (1H, dd), 2.87 (1H; dd), 3.71 (13H,
s), 4.21 (1H, m), 4.52 (1H, m), 4.94 (1H, bs), 4.98 (1H, bs), 5.75
(1H, d, J 15.5), 5.81 (1H, d, J 11.5), 6.43 (1H, d, J 11.5), 6.84
(1H, dd, J 15.5 and 9 0).
Preparation 3: Compound 2ak (x=1)
The compound was prepared using the procedure of Preparation 2, but
using lak as starting material instead of laj. The product was not
obtained crystalline after this chromatographic purification,
.delta. (300 MHz) in agreement with assigned structure.
Procedure 1
Reduction of Compound 2 or 3 to the Corresponding Compound II
(Scheme 2)
To a stirred solution of 2 or 3 (5 mmol) in dry THF (25 ml) at
-70.degree. C. under N.sub.2 was added di-isobutylaluminium hydride
(1M solution in hexanes, 15 ml for compound 2; 8 ml for compound 3)
dropwise. After stirring for 30 minutes, methanol (3 ml) was added
dropwise, and the reaction mixture was allowed to warm up to room
temperature. EtOAc and water were added, and after stirring for an
additional 30 minutes, the organic phase was separated, washed with
brine, dried and concentrated to give II, which was optionally
purified by chromatography and/or recrystallisation.
Preparation 4: 1
1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(R)-(3'-hydroxyprop-1'(E)-enyl)-
9,10-secopregna-5(E),7(E), 10(19)-triene
The compound was prepared using Procedure 1 in which the starting
material was compound 2aj (x=1). The crude product was of
sufficient purity for use as starting material in Preparation 5. An
analytical sample was obtained by recrystallisation from
ether-MeOH; m.p. 118.degree.-120.degree. C.; .delta.(300 MHz) 0.05
(12H, bs), 0.55 (3H, s), 0.86 (9H, s), 0.89 (9H, s), 1.04 (3H, d, J
6), 1.10-2.20 (15H, m), 2.29 (1H, d), 2.54 (1H, dd), 2.87 (1H, m),
4.06 (2H, m), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, bs), 4.g8 (1H,
bs), 5.56 (2H, ml, 5.82 (1H, d, J 11.5), 6.44 (1H, d, J 11.5).
Preparation 5: Compound 3aj (x =1)
Pyridinium dichromate (0.5 g) was added at room temperature to a
stirred solution of the compound from Preparation 4 (0.53 g) in
dichloromethane (10 ml). After stirring for 3 hours the mixture was
diluted with ether and filtered. The filtrate was concentrated in
vacuo and purified by chromatography (silica gel, hexane:ether 4:1
as eluant) to give 3aj (x=1) which crystallized on treatment with
methanol. M.p.: 101.degree.-103.degree. C.; .delta.(300 MHz) 0.06
(12H, m), 0.59 (3H, s), 0.86 (9H,s), 0.89 (9H, s), 1.15 (3H, d, J
6.6), 1.20-2.10 (13H, m), 2.30 (1H, bd), 2.42 (1H, m), 2.55 (1H,
dd), 2.89 (1H, m), 4.21 (1H, m), 4.53 (1H, m), 4.94 (1H, m), 4.98
(1H, m), 5.82 (1H, d, J 11.4), 6.06 (1H, dd, J 15.6 and 7.8), 6.44
(1H, d, J 11.4), 6.71 (1H, dd, J 15.6 and 8.8), 9.48 (1H, d, J
7.8).
Preparation 6: Compound 2aj (x=2)
A mixture of laj (4.56 g),
3-(methoxycarbonyl)-2-propenyl-1-idene-triphenylphosphorane (3.03
g) and alcohol-free chloroform (12 ml) was heated at 62.degree. C.
with stirring under N.sub.2 while part of the chloroform was
evaporated in vacuo. The mixture was kept at 62.degree. C.
overnight, cooled and partitioned between ether and water. The
organic layer was dried and evaporated in vacuo. The resulting oil
was purified by chromatography (silica gel, hexane-ether 97:3 as
eluant) to give an oil which crystallized from ether/methanol.
M.p.: 99.degree.-101.degree. C.; .lambda..sub.max =268 nm
(.epsilon.=52372); .delta.(300 MHz) 0.05 (12H, m), 0.56 (3H, s),
0.85 (9H, s), 0.89 (9H, s), 1.07 (3H, d, J 6.69), 1.17-2.10 (13H,
m), 2.25 (2H, m), 2.55 (1H, dd), 2.87 (1H, m), 3.73 (3H, s), 4.21
(1H, m), 4.52 (1H, m), 4.94 (1H, m), 4.98 (1H, m), 5.78 (1H, d, J
15.3), 5.81 (1H, d, J 11.4), 6.05 (2H, m), 6.44 (1H, d, J 11.4 ),
7.24 (1H, dd).
Preparation 7: Compound 2aj (x=3) Isomers A and B
A mixture of 3aj (x=1) (1 g),
3-(methoxycarbonyl).TM.2-propenyl-1-idene-triphenylphosphorane
(1.26 g) and alcohol-free chloroform (3 ml) was heated with
stirring at 62.degree. C. while part of the chloroform was
evaporated in vacuo. After 2 hours at 62.degree. C. the mixture was
cooled and partitioned between ether and water. The organic layer
was dried, concentrated and purified by chromatography (silica gel,
hexane-ether 9 1 as eluant). The first eluted title compound was
isomer B; .delta.(300 MHz) 0.06 (12H, m), 0.58 (3H, s), 0.86 (9H,
s), 0.89 (9H, s), 1.08 (3H, d, J 6,6) 1.17-2.35 (15H, m), 2.58 (1H,
dd), 2.88 (1H, m), 3.75 (3H, s), 4.21 (1H, m), 4.53 (1H, m), 4,94
(1H, m), 4.98 (1 H, m), 5.82 (3H, m), 5.98 (1H, t, J 11.2), 6.26
(1H, t, J 11.2), 6.45 (1H, d, J 11.3), 6.57 (1H, dd), 7.75 (1H, m).
The second eluted title compound was isomer A; .delta. (300 MHz)
0.05 (12H, m), 0.56 (3H, s), 0.86 (9H, s), 0.89 (9H, s), 1.07 (3H,
d, J 6,6), 1.15-2.35 (15H, m), 2.55 (1H, dd), 2.87 (1H, m), 3.73
(3H, s), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m), 4.98 (1H, m),
5.81 (3H, m), 6.07 (1H, dd), 6.20 (1H, dd), 6.48 (2H, m), 7.29 (1H,
dd).
Procedure 2
Reaction of Compound 3 with side chain fragment A'(Z=Ph.sub.3
P.sup..sym. --Ch.sup..crclbar.) to give Compound III (Scheme 2)
A stirred mixture of 3 and a molar excess of A' in toluene (5-10 ml
per gram 1) was heated under reflux under an N.sub.2 atmosphere
until a reasonable or complete conversion of 3 was obtained (4 to
16 hours). After cooling, the mixture was filtered, and the
filtrate concentrated and purified by chromatography (5-20% ether
in hexane or petroleum ether for the examples of Table 2) to give
III.
Preparation 8: Compound 101j
Using the method of Procedure 2, a mixture of 3aj (x=1) (0.6 g) and
cyclopropylcarbonylmethylenetriphenylphosphorane (5a) (0.86 g) and
toluene (4 ml) was stirred at 110.degree. C. for 4 hours. After
cooling to room temperature and filtration, the filtrate was
concentrated in vacuo and purified by chromatography (silica gel,
hexane-ether 85:5 as eluant) to give 101j as an oil which
crystallized from methanol. M.p.: 106.degree.-108.degree. C.;
.lambda..sub.max 279 2 nm (.delta.=50220); .delta.(300 MHz) 0.05
(12H, m), 0.56 (3H, s), 0.86 (9H, s), 0.89 (9H, s), 0.80-0.95 (2H,
m), 1.00-1.15 (2H, m), 1.08 (3H, d, J 6.5), 1.17-2.35 (16H, m),
2.55 (1H, dd), 2.88 (1H, m), 4.21 (1H, m), 4.53 (1H, m), 4.93 (1H,
m), 4.98 (1H, m), 5.81 (1H, d, J 11.4), 6.12 (3H, m), 6.44 (1H, d,
J 11.4), 7.18 (1H, dd).
Procedure 3
Reduction of Compound III to Compound II (R.sup.1 =H) (Scheme
2)
Sodium borohydride (0.29 g) was added to an ice-cooled, stirred
solution of III (2.5 g) in tetrahydrofuran (8 ml) and 0.4M
CeCl.sub.3.7H.sub.2 O in ethanol (11.5 ml). Methanol (6 ml) was
added over 10 minutes and after stirring for a further 20 minutes
the mixture was partitioned between ethyl acetate and water. The
organic layer was washed with water, dried and concentrated in
vacuo. The residue was purified by chromatography to give the
compound II.
Preparation 9: Compounds 102j and 103j
Using the method of Procedure 3 (101j as starting material), two
isomers were isolated by chromatography (3% acetone in toluene as
eluant). First eluted isomer was 102j; .delta.(300 MHz) 0.05 (12H,
m), 0.20-0.40 (2H, m), 0.56 (3H, s), 0.45-0.60 (2H, m), 0.86 (9H,
s), 0.89 (9H, s), 1.05 (3H, d, J 6.6), 0.70-2.35 (17H, m), 2.56
(1H, dd), 2.87 (1H, m), 3.48 (1H, t), 4.21 (1H, m), 4.53 (1H, m),
4.93 (1H, m), 4.98 (1H, m), 5.56 (1H, dd, J 15 and 8.6), 5.65 (1H,
dd, J 15 and 6.6), 5.81 (1H, d, J 11.4), 5.97 (1H, dd, J 15 and
10.4), 6.17 (1H, dd, J 15 and 10.4), 6.45 (1H, d, J 11.4). Second
eluted isomer was 103j; .delta.(300 MHz) 0.05 (12H, m), 0.20-0.40
(2H, m), 0.56 (3H, s), 0.44-0.65 (2H, m), 0.86 (9H, s), 0.89 (9H, s
m), 2.56 (1H, dd), 2.87 (1H, m), 3.49 (1H, t), 4.21 (1H, m), 4.53
(1H, m), 4.94 (1H, m), 4.98 (1H, m), 5.57 (1H, dd, J 15 and 8.6),
5.66 (1H, dd, J 15 and 6.4), 5.81 (1H, d, J 11.4), 5.97 (1H, dd, J
15 and 10.4), 6.19 (1H, dd, J 15 and 10.4), 6.45 (1H, d, J
11.4).
Procedure 4
Reaction of Compound 2 or 3 with R.sup.1 Li to give Compound II
(Scheme 2)
Alkyl-lithium (in ether, 3 molar equivalents for compound 2; 1.5
molar equivalent for compound 3) was added dropwise at -45.degree.
C. to a stirred solution of compound 2 or 3 (0.16 g) in dry THF (5
ml). After a further 50 minutes at -45.degree. C. the mixture was
partitioned between ether and water. The organic layer was washed
with brine, dried, and concentrated. The residue was purified by
chromatography (silica gel) to give II.
Preparation 10 Compound 104j
The compound was prepared using procedure 4 in which the
alkyl-lithium was methyl-lithium (1.5M) and the starting material
was 2aj (x=2). (Eluant: hexane-ether; 85:15). 104j .delta.(300 MHz)
0.06 (12H, m), 0.56 (3H, s), 0.87 (9H, s), 0.90 (9H, s), 1.05 (3H,
d, J 6.6), 1.33 (6H, s), 1.15-2.35 (16H, m), 2.56 (1H, dd), 2.87
(1H, m), 4.21 (1H, m), 4.53 (1H, m), 4.94 (1H, m), 4.98 (1H, m),
5.56 (1H, dd, J 15 and 8.6), 5.70 (1H, d, J 15.3), 5.81 (1H, d, J
11.4), 5.95 (1H, dd, J 15 and 10.3), 6.15 (1H, dd, J 15 and 10.3),
6.45 (1H, d, J 11.4).
Preparation 11 Compound 105j
The compound was prepared using procedure 4 in which the
alkyl-lithium was ethyl-lithium (1.5M) and the starting material
was 2aj (x=2). (Eluant: hexane-ether; 85:15). The compound
crystallized from MeOH; m.p.: 84.degree.-85.degree. C.,
.lambda..sub.max 232 nm (.epsilon.=37350) and 269.5 nm
(.epsilon.=26900); 105j .delta.(300 MHz) 0.06 (12H, m), 0.56 (3H,
s), 0.86 (9H, s), 0.89 (9H, s), 0.86 (6H, t), 1.05 (3H, d, J 6.6),
1.20-2.20 (19H, m), 2.30 (1H, bd), 2.56 (1H, dd), 2.87 (1H, m),
4.21 (1H, m), 4.53 (1H, m), 4.94 (1H, m), 4.98 (1H, m), 5.52 (1H,
dd, J 15.3), 5.54 (1H, dd, J 15 and 8.6), 5.82 (1H, d, J 11.4),
5.97 (1H, dd, J 15 and 10.3), 6.15 (1H, dd, J 15 and 10.3), 6.45
(1H, d, J 11.4).
Preparation 12 Compound 106j
The compound was prepared using procedure 4 in which the
alkyl-lithium was methyl-lithium (1.5M) and the starting material
was 2aj (x=3) isomer A. (Eluant: hexane-ether; 85:15). 106j .delta.
(300 MHz) in agreement with structure.
Procedure 5
Preparation of Compounds V from Aldehyde (3) and Side Chain
Fragment B (Scheme 3)
A solution of lithium di-iso-propylamide (0.4M in THF-hexanes, 3:1)
was added dropwise via a syringe (10 minutes) to a solution of the
side chain fragment B in dry THF (8 ml), stirred at -25.degree. C.
under nitrogen. The resulting yellow solution was then cooled to
-40.degree. C., and a solution of the aldehyde (3) (2 mmol) in dry
THF (8 ml) was added dropwise (5 minutes). After stirring for 30
minutes, benzoyl chloride (0.6 ml) was added dropwise, and the
mixture was allowed to warm to 0.degree. C. for a further 30
minutes. The reaction mixture was treated with ether (10 ml ) and
water (1 ml) and partitioned between ethyl acetate (100 ml) and
water (50 ml). The organic layer was washed with brine, dried, and
concentrated in vacuo to give a crude oil containing compound IV (Y
=PhC(O)) as a mixture of diastereoisomers. This was dissolved in
ethyl acetate (5 ml) and diluted with methanol (50 ml, saturated
with and containing suspended disodium hydrogen phosphate). To the
ice-cooled mixture was added sodium amalgam (ca. 5% Na, 15 g), and
the reaction mixture was stirred at 5.degree. C. under nitrogen for
15 hours. The mixture was then partitioned between ethyl acetate
(200 ml) and water (200 ml) (decanting from the mercury), and the
organic layer was washed with brine, dried and concentrated in
vacuo. Purification of the residue by chromatography gave V.
Preparation 13 Compound 107j
This compound was prepared using Procedure 5 [aldehyde 3aj (x=1) a
starting material] in which the side chain fragment B was compound
11 (0.55 g) and 12 ml of the lithium di-iso-propylamide solution
was used. The intermediate IV has R.sup.3 =OH. The chromatography
was performed on 150 g silica gel using 10% ethyl acetate in
petroleum ether as eluant. 107j; .delta. 0.05 (6H, bs), 0.56 (3H,
s), 0.86 (9H, s), 0.89 (9H, s), 1.04 (3H, d, J 6), 1.1-2.70 (31H,
m), 2.86 (1H, bd), 4.21 (1H, bs), 4.52 (1H, m), 4.94 (1H, bs), 4.98
(1H, bs), 5.45-5.65 (2H, m), 5.82 (1H, d, J 11), 5.9-6.20 (2H, m),
6.44 (1H, d, J 11).
Procedure 6
Preparation of Compound II or V (R=k) from the Corresponding
Compound (R=j) (Scheme 4)
A mixture of anthracene (0.10 g), triethylamine (20 mg), and the
compound II or V (R=j) (0.20 g) in dichloromethane (15 ml), stirred
under an atmosphere of nitrogen in a Pyrex flask immersed in a
water bath at 20.degree. C., was illuminated with radiation from a
high pressure Hg lamp (type: Hanau TQ 718Z2) for 30 minutes. The
reaction mixture was filtered and concentrated in vacuo to give a
residue. This was purified by chromatography (30 g silica gel) to
give II or V (R=k).
Preparation 14 Compound 102k
The compound was prepared using Procedure 6 in which starting
material II was compound 102j. (Eluant: toluene-acetone, 97:3)
102k; .delta. (300 MHz) 0.05 (12H, s), 0.18-0.40 (2H, m), 0.54 (3H,
s), 0.45-0.65 (2H, m), 0.87 (18H, s), 1.04 (3H, d, J 7), 0.80-2.35
(16H, m), 2.44 (1H, dd), 2.80 (1H, bd), 2.58 (1H, m), 2.81 (1H, m),
3.49 (1H, t), 4.18 (1H, m), 4.36 (1H, m), 4.85 (1H, d, J 2), 5.17
(1H, m), 5.61 (2H, m), 5.97 (2H, m), 6.18 (2H, m).
Preparation 15 Compound 103k
The compound was prepared using Procedure 6 in which starting
material II was compound 103j. (Eluant: toluene-acetone, 97:3)
103k: .delta. (300 MHz) 0.05 (12H, s), 0.18-0.40 (2H, m), 0.54 (3H,
s), 0.45-0.65 (2H, m), 0.87 (18H, s), 1.04 (3H, d, J 7), 0.80-2.35
(16H, m), 2.44 (1H, dd), 2.80 (1H, bd), 2.81 (1H, m), 3.48 (1H, t),
4.16 (1H, m), 4.36 (1H, m), 4.85 (1H, m), 5.17 (1H, m), 5.61 (2H,
m), 5.97 (2H, m), 6.18 (2H, m).
Preparation 16 Compound 104k
The compound was prepared using Procedure 6 in which starting
material II was compound 104j. (Eluant: 25% ether in petroleum
ether) 104k; .delta. (300 MHz) 0.05 (12H, bs), 0.54 (3H, s), 0.88
(18H, s), 1.04 (3H, d, J 7), 1.32 (6H, s), 1.15-2.35 (16H, m,
including 1.19 (6H, s)), 2.20 (1H, dd, J 13 and 7), 2.43 (1H, dd),
2.81 (1H, m) 4.18 (1H, m), 4.36 (1H, m), 4.86 (1H, bd), 5.17 (1H,
dd), 5.55 (1H, dd), 5.69 (1H, d, J 15), 5.96 (2H, m), 6.22 (1H, d,
J 11),
Preparation 17 Compound 105k
The compound was prepared using Procedure 6 in which starting
material II was compound 105j. (Eluant: 25% ether in petroleum
ether) 105k; .delta. (300 MHz) 0.05 (12H, m), 0.54 (3H, s), 0.85
(6H, t), 0.87 (18H, s), 1.04 (3H, d), 1.15-2.15 (19H, m), 2.20 (1H,
dd), 2.43 (1H, dd), 2.82 (1H, bd), 4.18 (1H, m), 4.36 (1H, m), 4.85
(1H, m), 5.16 (1H, m), 5.51 (1H, d, J 15.3), 5.53 (1H, dd, J 15.0
and 8.7), 5.96 (1H, dd, J 15.0 and 13.0), 6.00 (1H, d), 6.14 (1H,
dd, J 15.3 and 10.3), 6.22 (1H, d).
Preparation 18 Compound 2bj (x=2)
Using the method of Preparation 6 and by starting from lbj (see
British patent application No. 8914963.7) instead of laj, compound
2bj was obtained as an oil which crystallized from ether/methanol.
M.p.: 108.degree.-110.degree. C.; .delta..sub.max =268 nm
(.epsilon.=50887); .delta. (300 MHz) 0.05 (12H, bs), 0.48 (3H, s),
0.86 (9H, s), 0.88 (9H, s), 0.97 (3H, d), 1.05-2.05 (13H, m), 2.20
(1H, m), 2.30 (1H, bd), 2.53 (1H, dd), 2.84 (1H, bd), 3.72 (3H, s),
4.21 (1H, m), 4.51 (1H, m), 4.92 (1H, bs), 4.97 (1H, bs), 5.77 (1H,
dd), 5.79 (1H, d), 5.95-6.15 (2H, m), 6.43 (1H, d), 7.25 1H.,
dd).
Preparation 19 Compound 113j
The compound was prepared using Procedure 4 in which the
alkyl-lithium was methyl-lithium, and the starting material was 2bj
(x=2). 113j crystallized from MeOH; .delta..sub.max 232 nm
(.epsilon.35228) and 269 nm (.epsilon.25416); .delta. (300 MHz)
0.05 (12H, m), 0.49 (3H, s), 0.85 (9H, s), 0.89 (9H, s), 0.94 (3H,
d, J 6.6), 1.34 (6H, s), 1.00-2.15 (15H, m), 2.30 (1H, bd), 2.55
(1H, dd), 2.85 (1H, bd), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m),
4.98 (1H, m), 5.55 (1H, dd), 5.68 (1H, d), 5.81 (1H, d, J 11.4),
5.91 (1H, dd), 6.15 (1H, dd), 6.45 (1H, d, J 11.4).
Preparation 20 Compound 113k
The compound was prepared using Procedure 6 in which starting
material II was compound 113j. (Eluant: hexane-ether 80:20) 113k;
.delta. (300 MHz) 0.05 (12H, m), 0.48 (3H, s), 0.85 (9H, s), 0.86
(9H, s), 0.93 (3H, d, J 6.6). 1.33 (6H, s), 1.00-2.15 (15H, m),
2.20 (1H, dd), 2.43 (1H, dd), 2.80 (1H, bd), 4.18 (1H, m), 4.35
(1H, m), 4.85 (1H, m), 5.17 (1H, m), 5.54 (1H, dd), 5.68 (1H, d),
5.91 (1H, dd), 5.99 (1H, d, J 11.3). 6.15 (1H, dd), 6.22 (1H, d, J
11.3).
Preparation 21 Compound 114j
The compound was prepared by following the procedure described in
Preparation 19 and by using ethyl-lithium instead of
methyl-lithium. (Eluant: hexane-ether 80:20) 14j; .delta. (300 MHz)
0.05 (12H, m), 0.50 (3H, s), 0.85 (6H, t), 0.85 (9H, s), 0.89 (9H,
s), 0.94 (3H, d, J 6.6), 1.05-2.15 (19H, m), 2.30 (1H, bd), 2.55
(1H, dd), 2.85 (1H, bd), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m),
4.97 (1H, m), 5.50 (1H, d), 5.53 (1H, dd), 5.80 (1H, d, J 11.5),
5.94 (1H, dd), 6.15 (1H, dd), 6.44 (1H, d, J 11.5).
Preparation 22 Compound 114k
The compound was prepared using Procedure 6 in which starting
material II was compound 114j. (Eluant: hexane-ether 90:10) 114k:
.delta. (300 MHz) 0.05 (12H, m). 0.4S 3H, s), 0.86 (6H, t), 0.87
(9H, s), 0.88 (9H, s), 0.94 (3H, d, J 6.6), 1.00-2.15 (19H, m),
2.20 (1H, dd), 2.43 (1H, dd), 2.79 (1H, bd), 4.18 (1H, m), 4.36
(1H, m), 4.85 (1H, m), 5.17 (1H, m), 5.50 (1H, d), 5.53 (1H, dd),
5.93 (1H, dd), 6.00 (1H, d), 6.14 (1H, dd), 6.22 (1H, d).
Preparation 23 Compound 117j
The compound was prepared using Procedure 1 in which the starting
material was compound 2bj (x=2). (Eluant: hexane-ether 70:30) 117j;
.delta. (300 MHz) 0.05 (12H, m), 0.49 (3H, s), 0.85 (9H, s), 0.89
(9H, s), 0.94 (3H, d, J 6.6), 1.05-2.17 (15H, m), 2.30 (1H, bd),
2.55 (1H, dd), 2.84 (1H, bd), 4.16 (2H, m), 4.21 (1H, m), 4.52 (1H,
m), 4.93 (1H, m), 4.97 (1H, m), 5.58 (1H, dd), 5.71 (1H, m), 5.81
(1H, d, J 11.4), 5.96 (1H, dd), 6.20 (1H, dd), 6.44 (1H, d, J
11.4).
Preparation 24 Compound 117k
The compound was prepared using Procedure 6 in which starting
material II was compound 117j. (Eluant: hexane-ether 70:30) 117k;
.delta. (300 MHz) 0.05 (12H, m), 0.48 (3H, s), 0.86 (9H, s), 0.87
(9H, s), 0.93 (3H, d), 1.02-2.15 (15H, m), 2.21 (1H, dd), 2.43 (1H,
dd), 2.80 (1H, bd), 4.16 (2H, bd), 4.19 (1H, m), 4.36 (1H, m), 4.85
(1H, m), 5.17 (1H, m), 5.57 (1H, dd), 5.70 (1H, m), 5.95 (1H, dd),
6.00 (1H, d), 6.20 (2H, m).
Preparation 25 Compound 119j
The compound was prepared using Procedure 4 in which the
alkyl-lithium was n-propyl-lithium and the starting material was
2aj (x=2). 119j; .delta. (300 MHz) 0.05 (12H, m), 0.55 (3H, s),
0.86 (9H, s), 0.89 (9H, s), 0.89 (6H, t), 1.05 (3H, d, J 6.6),
1.15-2.20 (23H, m), 2.30 (1H, bd), 2.55 (1H, dd), 2.87 (1H, bd),
4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.50 (1H,
dd), 5.54 (1H, d), 5.81 (1H, d, J 11.4), 5.95 (1H, dd), 6.13 (1H,
dd), 6.45 (1H, d, J 11.4).
Preparation 26 Compound 119k
The compound was prepared using Procedure 6 in which starting
material II was compound 119j. (Eluant: hexane-ether 85:15) 119k;
.delta. (300 MHz) 0.05 (12H, m), 0.54 (3H, s), 0.86 (18H, s), 0.89
(6H, t), 1.04 (3H, d, J 6.6), 1.15-2.15 (23H, m), 2.20 (1H, dd),
2.43 (1H, dd), 2.81 (1H, bd), 4.18 (1H, m), 4.35 (1H, m), 4.85 (1H,
m), 5.16 (1H, m), 5.52 (1H, dd), 5.53 (1H, dd), 5.94 (1H, dd), 6.00
(1H, d), 6.12 (1H, dd), 6.22 (1H, d).
Preparation 27 Compound 121k
Compound 121j was prepared by using Procedure 1 in which the
starting material was compound 2aj (x=2). The crude 121j was of
sufficient purity for use as starting material in Procedure 6 by
which method it was transformed into compound 121k. (Eluant:
hexane-ether 70:30). 121k; .delta. (300 MHz) 0.05 (12H, m), 0.54
(3H, s), 0.86 (18H, s), 1.04 (3H, d, J 6.6), 1.12-2.30 (16H, m),
2.44 (1H, dd), 2.82 (1H, bd), 4.15 (2H, m), 4.17 (1H, m), 4.36 (1H,
m), 4.85 (1H, m), 5.16 (1H, m), 5.57 (1H, dd), 5.70 (1H, m), 5.97
(1H, dd), 6.00 (1H, d), 6.18 (1H, dd), 6.22 (1 H, d).
Preparation 28 Compound 2ak (x=1)
Using the method of Preparation 2 and by starting from lak instead
of laj compound 2ak (x=1) was obtained as an oil. .delta. (300 MHz)
0.05 (12H, bs), 0.55 (3H, s), 0.87 (18H, s), 1.08 (3H, d),
1.15-2.10 (12H, m), 2.10-2.35 (3H, m), 2.44 (1H, dd), 2.82 (1H,
bd), 3.70 (3H, s), 4.18 (1H, m), 4.36 (1H, m), 4.83 (1H, bd), 5.16
(1H, bd), 5.74 (1H, d), 6.00 (1H, d), 6.22 (1H, d), 6.87 (1H,
dd).
Preparation 29 Compound 123k
The compound was prepared using Procedure 1 in which the starting
material was compound 2ak (x=1). (Eluant: hexane-ether 7 3). 123k;
.delta. (300 MHz) 0.05 (12H, m), 0.54 (3H, s), 0.87 (18H, s), 1.03
(3H, d, J 6.6), 1.12-2.30 (16H, m), 2.44 (1H, dd), 2.82 (1H, bd),
4.06 (2H, m), 4.18 (1H, m), 4.36 (1H, m), 4.85 (1H, m), 5.17 (1H,
m), 5.54 (2H, m), 6.00 (1H, d, J 11.2), 6.22 (1H, d, J 11.2).
Preparation 30 Compound 3ak (x=1)
Using the method of Preparation 5 (compound 123k as starting
material), compound 3ak (x=1) was prepared and purified by
chromatography (Eluant: hexane-ether 4 1). .delta. (300 MHz) 0.05
(12H, m), 0.57 (3H, s), 0.86 (18H, s), 1.14 (3H, d, J 6.6),
1.10-1.90 (12H, m), 1.98 (1H, bd), 2.21 (1H, dd), 2.43 (2H, m),
2.83 (1H, bd), 4.18 (1H, m), 4.36 (1H, m), 4.85 (1H, m), 5.17 (1H,
m), 6.04 (2H, m), 6.22 (1H, d, J 11.3), 6.70 (1H, dd), 9.47 (1H, d,
J 7.8).
Preparation 31 Compound 2ak (x=3)
30 This compound was prepared by using the method of Preparation 6
and by starting from 3ak (x=1) instead of laj. The reaction mixture
was only kept at 62.degree. C for 2 hours. Compound 2ak (x=3) was
isolated by chromatography. (Eluant: hexane-ether 4:1). .delta.
(300 MHz) 0.05 (12H, m), 0.55 (3H, s), 0.87 (18H, s), 1.06 (3H, d,
J 6.6), 1.15-2.30 (15H, m), 2.43 (1H, dd), 2.82 (1H, bd), 3.73 (3H,
s), 4.18 (1H, m), 4.35 (1H, m), 4.84 (1H, m), 5.16 (1H, m), 5.79
(1H, dd), 5.82 (1H, d), 5.95-6.25 (4H, m), 6.50 (1H, dd), 7.29 (1H,
dd).
Preparation 32 Compound 124k
The compound was prepared by following Procedure 4 and by using
methyl-lithium and 2ak (x=3) as starting material. (Eluant:
hexane-ether 4:1). .delta. (300 MHz) 0.05 (12H, m), 0.54 (3H, s),
0.86 (18H, s), 1.04 (3H, d, J 6.6), 1.33 (6H, s), 1.15-2.30 (16H,
m), 2.44 (1H, dd), 2.82 (1H, bd), 4.18 (1H, m), 4.36 (1H, m), 4.85
(1H, m), 5.16 (1H, m), 5.56 (1H, dd), 5.78 (1H, d), 5.92-6.30 (6H,
m).
Preparation 33 Compound 126k
The compound was prepared by following Procedure 4 and by using
ethyl-lithium and 2ak (x=3) as starting material. (Eluant:
hexane-ether 4:1). .delta. (300 MHz) 0.05 (12H, m), 0.54 (3H, s),
0.84 (6H, t), 0.87 (18H, s), 1.04 (3H, d, J 6.5), 1.00-2.30 (20H,
m), 2.44 (1H, dd), 2.81 (1H, bd), 4.18 (1H, m), 4.36 (1H, m), 4.85
(1H, m), 5.17 (1H, m), 5.56 (1H, dd), 5.59 (1H, d), 6.00 (2H, m),
6.16 (4H, m).
Preparation 34 Compound 128k
This compound was prepared using Procedure 1 in which the starting
material was compound 2ak (x=3). .delta. (300 MHz) 05 (12H, m),
0.54 (3H, s), 0.87 (18H, s), 1.04 (3H, d, J 6.6), 1.12-2.25 (16H,
m), 2.43 (1H, dd), 2.82 (1H, bd), 4.18 (3H, m), 4.36 (1H, m), 4.85
(1H, m), 5.16 (1H, m), 5.59 (1H, dd), 5.79 (1H, m), 5.90-6.30 (6H,
m).
Preparation 35 Compound 107k
This compound was prepared using Procedure 6 in which starting
material II was compound 107j. .delta. (300 MHz) 0.05 (12H, m),
0.54 (3H, s), 0.87 (18H, s), 1.04 (3H, d), 1.15-2.15 (22H, m), 2.21
(2H, d), 2.40 (1H, m), 2.82 (1H, bd), 4.18 (1H, m), 4.36 (1H, m),
4.85 (1H, m), 5.17 (1H, m), 5.51 (1H, dd), 5.60 (1H, m), 6.00 (3H,
m), 6.24 (1H, d).
Procedure 7 Preparation of Compound I from the Corresponding
Compound II or V (R=k) (Scheme 4)
A solution of the compound II or V (0.2 g) and
tetra-n-butylammonium fluoride trihydrate (0.4 g) in THF (10 ml)
was heated at 60.degree. C. under an atmosphere of nitrogen for 50
minutes. After cooling, the reaction solution was partitioned
between ethyl acetate (40 ml) and 2% sodium hydrogen carbonate
solution (30 ml), and the organic layer was washed with water and
brine, dried and concentrated. The residue was purified by
chromatography (30 g silica gel, ethyl acetate as eluant) to give
I.
The compounds of Examples 1-4 and 6-14 were prepared using
procedure 7. The respective starting materials II or V are given in
the Examples.
Example 1
20(R)-(5'-Cyclopropyl-5'-hydroxy-penta-1'(E),3'(E)-dien-1'-yl)-1(S),
3(R)-dihydroxy-9,10-secopregna-5(Z), 7(E),10(19)-triene (Isomer A)
(Compound 108)
Starting material 102k; .delta. (300 MHz) 0.20-0.40 (2H, m , 0.53
(3H, s), 0.46-0.65 (2H, m), 1.05 (3H, d, J 6.6), 0.90-2.20 (18H,
m), 2.31 (1H, dd), 2.60 (1H, m), 2.83 (1H, m), 3.49 (1H, t), 4.23
(1H, m), 4.43 (1H, m), 5.00 (1H, m), 5.33 (1H, m), 5.57 (1H, dd, J
15 and 8.7), 5.66 (1H, dd, J and 6.5), 5.97 (1H, dd, J 15 and
10.3), 6.01 (1H, d, J 11.2) 6.17 (1H, dd, J 15 and 10.3), 6.38 (1H,
d, J 11.2).
Example 2
20(R)-(5'
-Cyclopropyl-5'-hydroxypenta-1'(E),3'(E)-dien-1'-yl)-1(S),
3(R)-dihydroxy-9,10-secopregna-5(Z), 7(E),10(19)-triene (Isomer B)
(Compound 109)
Starting material: 103k; .delta. (300 MHz) 0.22-0.40 (2H, m), 0.56
(3H, s), 0.46-0.65 (2H, m), 1.05 (3H, d, J 6.6), 0.90-2.20 (18H,
m), 2.31 (1H, dd), 2.60 (1H, m), 2.84 (1H, m), 3.50 (1H, t), 4.23
(1H, m), 4.43 (1H, m), 5.00 (1H, m), 5.33 (1H, m), 5.58 (1H, dd, J
15.1 and 8.6), 5.67 (1H, dd, J 15.2 and 6.3), 5.97 (1H, dd, J 15.1
and 10.3), 6.01 (1H, d, J 11.3) 6.19 (1H, dd, J 15.1 and 10.3),
6.38 (1H, d, J
Example 3 1
1(S),3(R)-Dihydroxy-20(R)-(5'-hydroxy-5'-methyl-hexa-1'(E),3'(E)-dien-l'-yl
)-9,10-secopregna-5(Z), 7(E)-10(19)-triene (Compound 110)
Starting material: 104k. Crystallisation from ethyl acetate-hexane
gave needles, m.p. 156.degree.-157.degree. C.; .lambda..sub.max 231
nm (.lambda.=42530) and 264 nm (.lambda.=18040); .delta. (300 MHz)
0.56 (3H, s), 1.05 (3H, d, J 6,6), 1.34 (6H, s), 1.15-2.20 (17H,
m), 2.31 (1H, dd), 2.60 (1H, dd), 2.84 (1H, m), 4.23 (1H, m), 4.43
(1H, m), 5.00 (1H, m), 5.33 (1H, m), 5.56 (1H, dd), 5.71 . (1H, dd,
J 15.4), 5.96 (2H, m), 6.16 (1H, dd), 6.38 (1H, d, J 11.2).
Example 4
1(S),3(R)-Dihydroxy-20(R)-(5'-ethyl-5'-hydroxy-hepta-1'(E),3'(E)-dien-1'-yl
)-9,10 -secopregna-5(Z),7(E), 10(19)-triene (Compound 111)
Starting material: 105k. Crystallisation from methyl format-hexane
gave needles, m.p. 123.degree.-125.degree. C.; .lambda..sub.max 232
nm (.lambda.=43745) and 264 nm (.lambda.=18060); .delta. (300 MHz)
0.55 (3H, s), 0.85 (6H, t), 1.04 (3H, d, J 6.6), 1.12-2.20 (21H,
m), 2.30 (1H, dd), 2.58 (1H, dd), 2.82 (1H, dd), 4.21 (1H, m), 4.41
(1H, m), 4.99 (1H, m), 5.31 (1H, m), 5.53 (2H, m), 5.95 (1H, dd, J
15 and 10.3), 6.00 (1H, d, J 11.3), 6.14 (1H, dd, J 15 and 10.3),
6.37 (1H, d, J 11.3).
Example 5 1
1(S),3(R)-Dihydroxy-20
(R)-(6'-hydroxy-hexa-1'(E),3'(E)-dien-1'-yl)-9,10-secopregna-5(Z),7(E),10(
19)-triene (Compound 112)
A solution of MC 903 [M. J. Calverley, Tetrahedron 43, (1987)](0.45
g) in a mixture of alcohol-free chloroform (20 ml) and
trifluoroacetic anhydride (9 ml) was kept at room temperature for
50 minutes. The reaction mixture was then slowly added to an
ice-cold stirred solution of potassium hydroxide (19.8 g) in
methanol (150 ml). After stirring for 10 minutes and concentration
in vacuo, the residue was partitioned between methylene chloride
and water. The organic layer was dried and concentrated.
Purification by chromatography (silica gel, hexane-ethyl acetate
1:3 as eluant) gave the title compound which crystallized from
ethyl acetate, m.p.: 132.degree.-35.degree. C; .lambda..sub.max
=232 nm (.lambda.=40980) and 264 nm (.lambda.=17494); .delta.(300
MHz) 0.56 (3H, s), 1.04 (3H, d, J 6.6), 1.15-2.25 (17H, m), 2.32
(3H, m), 2.60 (1H, dd), 2.82 (1H, dd), 3.66 (2H, m), 4.22 (1H, m),
4.43 (1H, m), 4.99 (1H, s), 5.32 (1H, s), 5.50 (2H, m), 6.00 (3H,
m), 6.37 (1H, d, J 11.2):
Example 6 1
1(S),3(R)-Dihydroxy-20(R)-(6'-hydroxy-6'-methyl-hepta-1'(E),3'(E)-dien-1'-y
l)-9,10-secopregna-5(Z), 7(E)-10(19)-triene (Compound 133)
Starting material: 107k; Crystallization from methyl
formate-hexane, m.p. 147.degree.-148.degree. C.; .lambda..sub.max
233 nm (.lambda.=43322) and 264 nm (.lambda.=17916); .delta.(300
MHz) 0.56 (3H, s), 1.05 (3H, d), 1.22 (6H, s), 1.20-2.20 (17H, m),
2.23 (2H, d), 2.31 (1H, dd), 2.60 (1H, dd), 2.83 (1H, bd), 4.23
(1H, m), 4.43 (1H, m), 5.00 (1H, m), 5.32 (1H, m), 5.50 (1H, dd),
5.60 (1H, m), 6.01 (3H, m), 6.38 (1H, d).
Example 7
1(S),3(R)-Dihydroxy-20(R)-(7'-hydr-oxy-hepta-1'(E),3'(E),5'(E)-trien-1'-yl)
-9,10-secopregna-5(Z),7(E),-10(19)-triene (Compound 129)
Starting material: 128k; .delta.(300 MHz) 0.59 (3H, s), 1.Q6 (3H,
d, J 6.6), 1.89 (2H, t), 1.15-2.21 (15H, m), 2.25 (1H, dd), 2.52
(1H, dd), 2.87 (1H, bd), 4.09 (2H, bd), 4.12 (1H, m), 4.35 (1H, m),
4.89 (1H, m), 5.28 (1H, m), 5.56 (1H, dd), 5.75 (1H, m), 5.95-6.36
(6H, m).
Example 8
1(S),3(R)-Dihydroxy-20(S)-(5'-hydroxy-5'-methyl-hexa-1'(E),3'(E)-dien-1'-yl
)-9,10-secopregna-5(Z), 7(E),10(19)-triene (Compound 115)
Starting material: 113k. The compound crystallized from ethyl
acetate-hexane, m.p. 98.degree.-102.degree. C.; .lambda..sub.max
232 nm (.epsilon.=and 265 nm (.epsilon.=17418); .delta.(300 MHz)
0.50 (3H, s), 0.94 (3H, d, J 6.6), 1.35 (6H, s), 1.05-2.15 (17H,
m), 2.31 (1H, dd), 2.57 (1H, bd), 2.82 (1H, bd), 4.22 (1H, m), 4.43
(1H, m), 5.00 (1H, m), 5.33 (1H, m), 5.56 (1H, dd), 5.69 (1H, d),
5.92 (1H, dd), 6.01 (1H, d, J 11.3), 6.16 (1H, dd), 6.37 (1H, d, J
11.3).
Example 9
1(S),3(R)-Dihydroxy-20(S)-(5'-ethyl-5'-hydroxy-hepta-1'(E),3'(E)-dien-1
'-yl)-9,10-secopregna-5(Z),7(E), 10(19)-triene (Compound 116)
Starting material: 114k; .lambda..sub.max 233 and 264 nm;
.delta.(300 MHz) 0.51 (3H, s), 0.87 (6H, t), 0.95 (3H, d, J 6.7),
1.02-2.15 (21H, m), 2.31 (1H, dd), 2.60 (1H, bd), 2.81 (1H, bd),
4.23 (1H, m), 4.43 (1H, m), 5.00 (1H, m), 5.33 (1H, m), 5.51 (1H,
d), 5.53 (1H, dd), 5.95 (1H, dd), 6.01 (1H, d), 6.16 (1H, dd), 6.38
(1H, d, J 11.2).
Example 10
1(S),3(R)-Dihydroxy-20(S)-(5'-hydroxy-penta-1'(E),3'(E)-dien-1'-yl-9,10-sec
opregna-5(Z),7(E), 10(19)-triene (Compound 118)
Starting material: 117k; .delta.(300 MHz) 0.50 (3H, s), 0.94 (3H,
d, J 6.6), 1.02-2.20 (17H, m), 2.31 (1H, dd), 2.59 (1H, dd), 2.81
(1H, bd), 4.17 (2H, bd), 4.23 (1H, m), 4.42 (1H, m), 5.00 (1H, m),
5.33 (1H, m), 5.58 (1H, dd), 5.72 (1H, m), 5.96 (1H, dd), 6.01 (1H,
d, J 11.3), 6.21 (1H, dd), 6.37 (1H, d, J 11.3).
Example 11
1(S),
3(R)-Dihydroxy-20(R)-(5'-hydroxy-5,-n-propyl-octa-1'(E),3'(E)-dien-1'-yl)-
9,10-secopregna-5(Z), 7(E),10(19)-triene (Compound 120)
Starting material: 119k; .delta.(300 MHz) 0.55 (3H, s), 0.89 (6H,
t), 1.04 (3H, d, J 6.6), 1.15-2.18 (25H, m), 2.30 (1H, dd), 2.59
(1H, dd), 2.82 (1H, bd), 4.21 (1H, m), 4.41 (1H, m), 4.98 (1H, m),
5.31 (1H, m), 5.52 (1H, dd), 5.54 (1H, d), 5.93 (1H, dd), 6.00 (1H,
d) 6.12 (1H, dd), 6.36 (1H, d, J 11.2).
Example 12
1(S),3(R)-Dihydroxy-20(R)-(5'-hydroxy-penta-1'(E),3'(E)-dien-1"-yl-9,10-sec
opregna-5(Z),7(E), 10(19)-triene (Compound 122)
Starting material: 121k. Crystals from methyl formate; m.p.:
154.degree.-155.degree. C.; .lambda..sub.max 231 nm
(.epsilon.=41228) and 264 nm (.epsilon.=17876); .delta.(300 MHz)
0.58 (3H, s), 1.05 (3H, d, J 6.6), 1.15-1.80 (12H, m), 1.89 (2H,
t), 2.01 (2H, m), 2.14 (1H, m), 2.26 (1H, dd), 2.52 (1H, dd), 2.87
(1H, bd), 4.06 (2H, m), 4.12 (1H, m), 4.35 (1H, t), 4.89 (1H, m),
5.28 (1H, m), 5.53 (1H, dd), 5.67 (1H, d), 5.98 (1H, dd), 6.08 (1H,
d, J 11.2), 6.16 (1H, dd), 6.32 (1H, d, J 11.2).
Example 13
1(S),3(R)-Dihydroxy-20(R)-(7'-hydroxy-7'-methyl-octa-1'(E),3'(E)-5'(E)-trie
n-1'-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 125
Starting material: 124k. Compound 125 was crystallized from methyl
formate; .lambda..sub.max 259 nm (E =53692), nm (.epsilon.=67103),
and 279 nm (.epsilon.=53256); .delta.(300 MHz) 0.56 (3H, s), 1.05
(3H, d, J 6.6), 1.34 (6H, s), 1.15-2.20 (17H, m), 2.31 (1H, dd),
2.60 (1H, bd), 2.83 (1H, bd), 4.22 (1H, m), 4.42 (1H, m), 4.99 (1H,
m), 5.32 (1H, m), 5.57 (1H, dd), 5.79 (1H, d), 5.90-6.30 (5H, m),
6.38 (1H, d, J
Example 14
1(S),3(R)-Dihydroxy-20(R)-(7'-hydroxy-7'-ethyl-nona-1'(E),3'(E)-5'(E)-trien
-1'-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 127
Starting material 126k. Crystals from methyl formate-hexane; m.p.:
115.degree.-118.degree. C. .lambda..sub.max 260 nm
(.epsilon.=58040), 270 nm (.epsilon.=72111), and 281 nm
(.epsilon.=56714); .delta.(300 MHz) 0.56 (3H, s), 0.85 (6H, t),
1.05 (3H, d, J 6.6), 1.15-2.20 (21H, m), 2.31 (1H, dd), 2.60 (1H,
dd), 2.83 (1H, bd), 4.22 (1H, m), 4.42 (1H, m), 5.00 (1H, m), 5.32
(1H, m), 5.59 (1H, dd), 5.61 (1H, d), 6.00 (2H, m), 6.10-6.30 (3H,
m), 6.37 (1H, d, J 11.3).
Example 15
20(S)-(5'-Cyclopropyl-5'-hydroxy-penta-1'(E),3'(E)-dien-1'-yl)-1(S),
3(R)-dihydroxy-9,10-secopregna-5(Z), 7(E),10(19)-triene (Compounds
131 and 132)
These two isomeric compounds are prepared by using the procedures
described in Preparations 8, 9, 14, 15 and Examples 1 and 2 and by
substituting 3b (x=1) (described in British patent application No.
8914963.7) for 3aj (x=1) in Preparation 8.
Example 16
1S),3(R)-Dihydroxy-20(S)-(6'-hydroxy-hexa-1'(E),3'(E)-dien-1'-yl)-9,10-seco
pregna-5(Z),7(E),10(19)-triene (Compound 130)
This compound was prepared by following the procedure described in
Example 5 and by using
20(S)-(3'-cyclopropyl-3'-hydroxyprop-1'(E)-enyl)-1(S),3(R)-dihydroxy-9,10-
secopregna-5(Z),7(E),10(19)-triene - isomer A or isomer B or
mixtures thereof - (described in British patent application No.
8914963.7) as starting material instead of MC 903.
.delta.(300 MHz) 0.50 (3H, s), 0.93 (3H, d), 1.05-2.10 (17H, m),
2.30 (1H, m), 2.34 (2H, q), 2.58 (1H, dd), 2.81 (1H, bd), 3.67 (2H,
t), 4.22 (1H, m), 4.42 (1H, m), 4.99 (1H, bs), 5.32 (1H, bs),
5.45-5.60 (2H, m), 5.85-6.15 (3H, m), 6.37 (1H, d).
Example 17
1(S),3(R)-Dihydroxy-20(S)-(6'-hydroxy-6'-methyl-hepta-1'(E),3'(E)-dien-1'-y
l)-9,10-secopregna-5(Z), 7(E),10(19)-triene (Compound 134)
This compound is prepared by using the procedure described in
Preparations 13 and 35 and Procedure 7 and by substituting 3bj
(x=1) (described in British patent application No. 8914963.7) for
3aj (x=1) in Preparation 13.
Example 18
1(S),3(R)-Dihydroxy-20(S)-(6'-ethyl-6'-hydroxy-octa-1'(E),3'(E)-dien-1'-yl)
-9,10-secopregna-5(Z), 7(E),10(19)-triene (Compound 135)
This compound is prepared by using the procedure described in
Example 17 but substituting compound 12 for compound 11 in
Preparation 13.
Example 19
1(S),3(R)-Dihydroxy-2O(R)-(6'-ethyl-6'-hydroxy-octa-1'(E),3'(E)-dien-1'-yl)
-9,10-secopregna-5(Z), 7(E),10(19)-triene (Compound 136)
This compound is prepared by using the procedure described in
Preparations 13 and 35 and Procedure 7 but substituting compound 12
for compound 11 in Preparation 13; .delta.(300 MHz) 0.56 (3H, s),
0.88 (6H, t), 1.04 (3H, d), 7 30 1.48 (4H, q), 1.15-2.17 (17H, m),
2.20 (2H, d), 2.32 (1H, dd), 2.60 (1H, dd), 2.83 (1H, dd), 4.23
(1H, m), 4.43 (1H, m), 5.00 (1H, m), 5.32 (1H, m), 5.52 (2H, m),
6.00 (3H, m), 6.38 (1H, d).
Example 20
1(S),3(R)-Dihydroxy-20-(5',6'-dimethyl-6'-hydroxy-hepta-1'(E),3
(E)-dien-1'-yl)-9,10-secopregna-5(Z), 7(E),10(l9)-triene (Compounds
137-140)
The four diastereoisomers of the title compound are prepared
separately using the methods of Procedures 5, 6 and 7 and the
appropriate starting materials 3aj (x=1) or bj (x=1) and 17 or
18.
Example 21
Dermatological Cream Containing Compound 111
In 1 g almond oil was dissolved 0.1 mg 111. To this solution was
added 40 g of mineral oil and 20 g of self-emulsifying beeswax. The
mixture was heated to liquify. After the addition of 40 ml hot
water, the mixture was mixed well. The resulting cream contains
approximately 1 .mu.g of 111 per gram of cream.
Example 22
Capsules containing Compound 111
111 was suspended in arachis oil to a final concentration of 5
.mu.g 111/ml oil. 10 Parts by weight of gelatine, 5 parts by weight
glycerine, 0.08 parts by weight potassium sorbate, and 14 parts by
weight distilled water were mixed together with heating and formed
into soft gelatine capsules. These were then filled each with 100
.mu.l of the 111 in oil suspension, such that each capsule
contained 0.5 .mu.g 111.
* * * * *